Attaining control over specific neural processes can enable people to influence associated perceptions, behaviors, and cognitions, with potential clinical application to a range of brain- based disorders, including substance abuse (SA). Using real-time fMRI (rtfMRI), our team recently demonstrated that such control can be learned in the anterior cingulate cortex (ACC), leading to clinically significant reductions in pain. If this exciting initial finding can be generalized to SA, it would have major implications for clinical intervention. Our proposal attempts to take a major step in this direction, which seems likely to be productive given that during rtfMRI of the ACC, we identified activated brain regions involved in SA related reward driven behavior. To make rtfMRI a more useful clinical tool, we propose to resolve four potentially problematic issues identified in our prior rtfMRI studies. First, optimal regions for feedback control need to be determined. Second, subjects employ different cognitive strategies to modulate brain activity, producing variability in brain regions activated and subsequent efficacy in learned control. Third, the strength of connectivity between brain regions may influence cognitive processes and may be a better target for learned control. Fourth, there are significant individual differences in how well subjects are able to modulate their brain activity. We plan to address these issues in the following aims: (1) Enhance and test a system to perform real-time control of brain activity and strength of connectivity between multiple SA and pain related brain regions;(2) Determine optimal cognitive strategies (distraction and reappraisal), and individual differences in ability to control distributed brain regions;(3) Characterize the learned control of the strength of brain connectivity;and (4) Pilot the optimized rtfMRI parameters in a group of SA patients. Our overall goals are to develop rtfMRI as an efficacious clinical therapy for patients with SA and other brain disorders. PUBLIC HEALTH RELEVANCE: Substance abuse is a highly prevalent and debilitating condition that presents a terrible burden to affected patients, their families, and society as a whole, resulting in enormous economic costs. Completion of the proposed aims will lead to an improved understanding of brain modulatory systems. This will also introduce a potentially novel clinical therapy for substance abuse patients as well as patients with overlapping central nervous system illnesses, including chronic pain conditions, depression, and anxiety.